Osteoarthritis (OA) is the most common joint disease, currently affecting approximately 40 million Americans. The central pathogenetic mechanism in OA is an aberrant cartilage matrix remodeling process with loss of cartilage cells and matrix, resulting in biomechanical joint failure and inflammation. Loss of glycosaminoglycans precedes the degradation of cartilage matrix proteins and appears to be more readily reversible. However, therapeutic approaches targeting this process have not been pursued. In preliminary studies we have identified hexosaminidase as the major glycosaminoglycan degrading enzyme in cartilage and developed OPT-66, a novel potent and specific inhibitor of this enzyme. OPT-66 completely prevented loss of glycosaminoglycans in cultured cartilage. [unreadable] [unreadable] Based on these findings and preliminary in vivo data we propose the hypothesis that hexosaminidase inhibitors represent a novel approach to chondroprotection. [unreadable] [unreadable] The specific aims are: [unreadable] 1. Prepare sustained release formulations of OPT-66 and determine intraarticular retention time. [unreadable] 2. Assess efficacy of OPT-66 formulations in comparison to untreated, saline injected and hyaluronan-treated animals. [unreadable] Efficacy of OPT-66 is defined as significant reduction in: [unreadable] (i) histologic scores by at least 2 grades; [unreadable] (ii) lesion surface by at least 30%; [unreadable] (iii) loss of safranin O staining by at least 20%; [unreadable] (iv) biochemical markers of cartilage degradation. [unreadable] [unreadable] [unreadable]